Obesity produces a variety of metabolic disorders that are devastating to the cardiovascular system. Many of these pathologies can be explained by an obesity-induced activation of the sympathetic nervous system. The hypothesis that obesity increases sympathetic nerve activity (SNA) is based on the following evidence: (1) overweight results in chronic elevations in leptin and insulin; (2) leptin and insulin penetrate into the brain where they bind with their specific receptors located in cardiovascular control centers; (3) acute brain administration of leptin and insulin elicits increases in SNA; (4) both leptin and insulin activate intracellular phosphoinosital-3 kinase (PI3K); and (5) pharmacological blockade of brain PI3K abolishes SNA increases to leptin and insulin. Despite the importance of obesity-induced sympathetic activation, a number of key questions remain to be answered. For example, the specific brain sites that respond to insulin and leptin to increase PI3K and activate sympathetic activity remain to be determined. In addition, it is not known whether chronic increases in leptin and insulin, as occur in obesity, cause chronic elevations in SNA. Finally, it is not known whether chronic PI3K blockade can chronically inhibit the sympathetic increases that occur during hyperleptinemia and hyperinsulinemia in the course of high-fat diet-induced obesity. [unreadable] [unreadable] To answer these questions, the proposed studies will examine whether selective microinjection of PI3K antagonists into the arcuate nucleus will abolish increases in sympathetic nerve activity to systemic insulin and leptin. Second, we will determine whether chronic intracerebroventricular infusion of leptin or insulin produce long-term elevations in SNA measured continuously by telemetry. Third, we will establish whether increases in leptin and insulin, secondary to a high-fat diet, will produce chronic increases in SNA and blood pressure that are abolished by intracerebroventricular blockade of PI3K. By demonstrating the mechanisms of obesity-induced sympathetic activation, these experiments will provide a better understanding of central neural regulation of autonomic output, and will unravel the mechanisms by which weight gain increases sympathetic activity, alters renal function, and raises blood pressure. Furthermore, new information from these studies about pharmacological blockade of brain leptin and insulin signaling may lead to novel therapeutic strategies for obesity-induced cardiovascular disease. [unreadable] [unreadable] [unreadable]